SUMMARY Shigellosis (bacillary dysentery) is a severe bloody diarrhea that occurs worldwide and for which there is no licensed vaccine. This disease is particularly devastating in low income regions of the world where clean water and proper sanitation are lacking. Mortality and morbidity are highest in children under the age of 5 with survivors exhibiting impaired growth due to malnutrition. Shigella spp. are also common pathogens associated with diarrheal outbreaks in crowded settings such as among refugees and military personnel. Indeed, it was recently reported that the U.S. had lost 1 million service days in Iraq and Afghanistan due to Shigella spp. The Shigella spp. invasive phenotype requires a type III secretion system (T3SS) and the T3SS apparatus (T3SA), which resembles a molecular syringe and needle, is the energized conduit that delivers effector proteins directly into target cells to hijack normal cellular functions. A needle tip protein, IpaD, and the first translocator protein, IpaB, localize to the distal end of the T3SA needle. IpaB and IpaD are required for pathogenesis and each is highly conserved among the shigellae (being 97% and 91% identical among all virulent Shigella strains, respectively). The genus Shigella includes four species but >58 serotypes with new serotype variants continually emerging. Thus, we have developed a serotype-independent vaccine by genetically fusing IpaB and IpaD to produce the novel fusion protein, DBF. DBF, admixed with dmLT (the adjuvant double-mutant labile toxin from Enterotoxigenic E. coli and delivered intranasally or parenterally, protected mice against lethal challenges by homologous S. flexneri and heterologous S. sonnei and S. dysenteriae. Furthermore, DBF+dmLT administered parenterally protected 80% of monkeys from severe diarrhea after the heterologous S. sonnei challenge. Unfortunately, humans typically do not respond well to recombinant antigens of a monomeric nature. Therefore, we have developed hyaluronan polyvalent adjuvant fusion technology (Haf), a complex nanoparticle containing a carrier, adjuvant, and the fusion antigen. With this technology, the loaded nanoparticle is targeted for capture by dendritic cells, which deliver the protein cargo to lymph nodes, mimicking a bacterial infection. The nanoparticles remain at the lymph node germinal centers for extended periods eliciting a stronger immune response than the monomer with prolonged memory. Thus, although DBF+dmLT has been shown to protect 80% of monkeys from severe diarrhea caused by S. sonnei, we hypothesize that the nanoparticle that is Haf-DBF will elicit a robust immune response by taking advantage of the ability of the hyaluronan component of Haf to invoke recruitment of antigen- presenting cells (APCs), increased lymphoid tissue exposure of adjuvant/antigen, and Haf-mediated clustering of antigen to mimic a natural infection.